1. Field of the Invention
The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides benzimidazolone derivatives for the treatment of respiratory syncytial virus infection.
2. Background Art
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract infection in infants, children, elderly and immunocompromised persons. Severe infection of the virus may result in bronchiolitis or pneumonia which may require hospitalization or result in death. (JAMA, 1997, 277, 12). Currently only Ribavirin is approved for the treatment of this viral infection. Ribavirin is a nucleoside analogue which is administered intranasally as an aerosol. The agent is quite toxic, and its efficacy has remained controversial. RespiGam, approved for prophylaxis in high risk pediatric patients, is an intravenous immunoglobulin which effectively neutralizes the virus. Recently, Synagis, a monoclonal antibody administered through intramuscular injection has also been approved for use in high risk pediatric patients. However, both drugs are very expensive. Accordingly, inexpensive, safe and effective antiviral agents against respiratory syncytial virus will be beneficial for patients.
Many agents are known to inhibit respiratory syncytial virus (De Clercq, Int. J Antiviral Agents, 1996, 7, 193). Y. Tao et al. (EP 0 058 146 A1, 1998) disclosed that Ceterizine, a known antihistamine, exhibited anti-RSV activity. Tidwell et al., J. Med Chem. 1983, 26, 294 (U.S. Pat. No. 4,324,794, 1982), and Dubovi et al., Antimicrobial Agents and Chemotherapy, 1981, 19, 649, reported a series of amidino compounds with the formula shown below as inhibitors of RSV. 
Hsu et al., U.S. Pat. No. 5,256,668 (1993) also disclosed a series of 6-aminopyrimidones that possess anti-viral activity against RSV. 
Y. Gluzman, et al., (AU Patent, Au-A-14,704, 1997) and P. R. Wyde et al. (Antiviral Res. 1998, 38, 31) disclosed a series of triazine containing compounds that were useful for the treatment and/or prevention of RSV infection. 
In addition, T. Nitz, et al., (WO Patent, WO 00/38508, 1999) disclosed a series of triaryl containing compounds that were useful for the treatment and/or prevention of RSV and related pneumoviral infections. 
A related series of compounds were first disclosed by F. Pagani and F. Sparatore in Boll Chim Farm. 1965, 104, 427 and by G. Paglietti, et al. in Il Farmaco, Ed. Sci. 1975, 30, 505, and found to possess analgesic and anti-arrhythmic activity. The structural formula for these compounds are depicted in Formula Ia and Ib. 
In Formula Ia and Ib, A is xe2x80x94(CH2)n-N(R)2, n=2 or 3, Rxe2x95x90Me or Et, 
Another series of closely related compounds that Sparatore had disclosed were in Il Farmaco Ed. Sci. 1967, 23, 344 (U.S. Pat. No 3,394, 141, 1968). Some of the compounds were reported to have analgesic, anti-inflammatory or anti-pyretic activities. The structure of these compounds is depicted in formula Ic. In Formula Ic, Cxe2x95x90H, CF3, or N2. D is xe2x80x94(CH2)n-NR2, n=2 or 3, Rxe2x95x90Me or Et, or 
Another series of compounds structurally related to this invention are pyrido[1,2-a]benzoazoles and pyrimidio[1,2a]benzimidazoles disclosed by S. Shigeta et al in Antiviral Chem. and Chemother. 1992, 3, 171. These compounds have demonstrated inhibition of orthomyxovirus and paramyxovirus replication in HeLa cells. The structures of these compounds are shown in formulas Id and Ie, in which Rxe2x95x90NH, S, or O; Qxe2x95x90xe2x80x94NHCOPh, xe2x80x94COOH, COOEt, or CN; Txe2x95x90COMe, CN, or COOEt; G=O or NH. 
Another series of 2-aminobenzimidazoles have been reported by E. Janssens, et al. as inhibitors of RSV in a series of recent publications and representative examples formula 1f-1h are shown below from PCT WO 01/0061 1 A1; PCT WO 01/00612 and PCT WO 01/00615, respectively all published on Jan. 4, 2001.
A bis-benzimidazole with an ethylenediol linker shown below has also been reported as a potent inhibitor of rhinoviruses (Roderick, et al. J. Med Chem. 1972, 15, 655.
Other structurally related compounds are bis-benzimidazoles which possess antifungal activity (B. Cakir, et al. Eczacilik Fak. Derg. 1988, 5, 71.
Also, H. R. Howard et al. reported a series of benzimidazolone-1-acetic acids that possessed aldolase reductase inhibitory activity (Eur. J. Med. Chem. 1992, 27, 779-789). 
Other prior art related to the chemical structure of the present invention:
(1) F. Sparatore, et al, xe2x80x9cDerivati Benzotriazolici Attivi Sullxe2x80x2accrescimento Delle Piante,xe2x80x9d Il Farmaco Ed. Sci. 1978, 33, 901.
(2) Katritzky, A. R. et al, xe2x80x9cSynthesis and Transformations Of Substituted Benzazolyl- and Tetrazolyl(benzotriazol-1-yl)methanes,xe2x80x9d J. Heterocyclic Chem. 1996,33,1107.
(3) Terri A. Fairley, et al. xe2x80x9cStructure, DNA Minor Groove Binding, And Base Pair Specificity of Alkyl and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles), J. Med Chem. 1993, 36, 1746.
(4) R. K. Upadhyay et al, xe2x80x9cNew Synthesis and Biological Evaluation,xe2x80x9d Indian J Heterocyclic Chem. 1994, 4, 121.
(5) A. R. Katritzky, et al, xe2x80x9cA New Route to N-substituted Heterocycles,xe2x80x9d Tetrahedron, 1993, 49, 2829.
(6) K. Yu et al. in Substituted Benzimidazole Anti-viral Agents, PCT WO 00/04900 published February 3, 2000.
This invention relates to the antiviral activity against RSV found in a series of 1-substituted 2-(3xe2x80x2-N-substituted 2-oxo-benzimidazolylmethyl)-benzimidazoles. The structural formula for these compounds are depicted in Formula 1, and includes pharmaceutically acceptable salts thereof. 
wherein:
R1 is xe2x80x94(CRvRw)nxe2x80x94X;
Rv and Rw are independently selected from the group consisting of H, C1-6alkyl, and C2-6alkenyl; optionally substituted with 1-6 of the same or different halogen;
X is H, C1-6alkyl, C2-6alkenyl; each of said C1-6alkyl, C2-6alkenyl being optionally substituted with (1) one to six same or different halogen or hydroxy; (2) a member selected from the group consisting of phenyl, xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94CH(OH)-Ph, -Ph-S(O)2C1-6alkyl, 
(3) a member from Group A1;
Group A1 is CN, ORxe2x80x2, NRxe2x80x2Rxe2x80x3, Rxe2x80x2NCORxe2x80x3, NRxe2x80x2CONRxe2x80x3Rxe2x80x2xe2x80x3, NRxe2x80x2SO2Rxe2x80x3, NRxe2x80x2COORxe2x80x3, CORxe2x80x2, COORxe2x80x2, OS(O)2Rxe2x80x2, S(O)tRxe2x80x2 or PO(ORxe2x80x2)2;
n is 1-6;
tis0-2;
R2 is
(i) H, C1 alkyl, C2-6alkenyl, phenyl, or a functionality selected from Group A2 or Group B; each of said C1-6alkyl, C2-6 alkenyl, and phenyl being optionally substituted with (1) one to six same or different halogen or hydroxy or (2) one to two same or different members of Group A or Group B;
(ii) xe2x80x94(CRxRY)nxe2x80x2, xe2x80x94(CO)pxe2x80x94C6 H4-(Z1)(Z2), wherein Z1 and Z2 are each independently selected from the group consisting of Group A, Group B, and xe2x80x94(CH2)nxe2x80x2xe2x80x94Zxe2x80x2; wherein said Zxe2x80x2 is heterocycle or xe2x80x94(NRdReRf)+(halogen)-; and the Z1 and Z2 groups may each be in the ortho, meta or para position relative to the xe2x80x94(CRxRY)nxe2x80x2xe2x80x94(CO)p-group; wherein Rd, Re and Rf are independently C1-6alkyl, C2-6alkenyl, OH or C1-6alkyl COOH;
p is 0 or 1;
nxe2x80x2 is 1-6; or
(iii) xe2x80x94(CRxRy)nxe2x80x3xe2x80x94heterocycle;
nxe2x80x3 is 0-6;
R3, R6, R7 and R10 are each independently H;
R5, R8 and R9 are each independently H, halogen or CF3;
R4 is selected from the group consisting of H, halogen, CN, xe2x80x94C(O)C1-6alkyl and 
xe2x80x83R11, R12 are each independently H;
Rx, Ry are each independently H or C1-6alkyl;
Group A2 is CORxe2x80x2, COORxe2x80x2, CONRRxe2x80x3xe2x80x3 or CONRxe2x80x2SO2Rxe2x80x3;
Group A3 is CN, N2, ORxe2x80x2, OCONRxe2x80x2Rxe2x80x3, NRxe2x80x2Rxe2x80x3, N(Rxe2x80x2) CORxe2x80x3, N(Rxe2x80x2)CONRxe2x80x3Rxe2x80x3xe2x80x2,
NRxe2x80x2SO2Rxe2x80x3, NRxe2x80x2COORxe2x80x3, SOmRxe2x80x2, SO2NRxe2x80x2Rxe2x80x3, SO2NRxe2x80x2CORxe2x80x3 or PO(ORxe2x80x2)2;
Group A is a member selected from Group A2 and Group A3;
Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 are each independently selected from the group consisting of H, C1-6alkyl, phenyl and heterocycle; and each of said C1-6alkyl, phenyl and heterocycle being optionally substituted with (1) one to six of same or different halogen or hydroxy; (2) one to two of the same or different members of Group Axe2x80x2 or Group B; or (3) heterocycle; or Rxe2x80x2and Rxe2x80x3 taken together form a 5 to 6 membered aromatic or non-aromatic ring containing one to four of the same or different heteroatoms selected from the group consisting of N, S and O;
Group Axe2x80x2 is halogen, CN, NO2, ORa, OCONRaRb, NRaRb, RaNCORb, NRaCONRbRc, NRaSO2Rb, NRaCOORb, CORxe2x80x2, CRcNNRaRb, CRaNORb, COORa, CONRaRb, CONRa SO2Rb, SOmxe2x80x2Ra, SO2NRaRb, SO2NRaCORb or PO(ORa)2;
Ra, Rb, Rc are each independently selected from the group consisting of H and C1-6alkyl;
Group B is xe2x80x94(CH2)nxe2x80x3xe2x80x2Q, xe2x80x94(CH2)nxe2x80x3SOmxe2x80x3xe2x80x94R13 or xe2x80x94COQ;
Q is an N-linked amino acid selected from the group consisting of alanine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, pipecolic acid, xcex1-amino-butyric acid, xcex1-amino-propanoic acid, 2-amino-3-phosphonopropionic acid and iminodiacetic acid; wherein Q is linked to the adjacent carbon atom in Group B through a nitrogen atom of said N-linked amino acid; wherein said N-linked amino acid includes D- or L-enantiomers or mixtures thereof;
R13 is selected from a group consisting of H and C1-6alkyl; said C, alkyl being optionally substituted with (1) one to five hydroxy groups or (2) two of the same or different functionalities selected from the group consisting of COORx and CONRxRy;
m, m and m are independently 0-2;
nxe2x80x2xe2x80x3 is 1-6;
heterocycle is a 5-6 membered aromatic or non-aromatic ring which contains one to four heteroatoms independently selected from the group consisting of O, N and S; wherein said aromatic or non-aromatic ring is optionally fused to a phenyl ring; wherein the aromatic or non-aromatic ring is optionally substituted with one to five of the same or different substituents selected from the group consisting of C1-6alkyl, Group A and Group B; and halogen is bromine, chlorine, fluorine or iodine.
In a preferred embodiment, the heterocycle is an aromatic ring selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indolizinyl, indolyl, isoindolyl, 3 H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1 H-indazolyl, benzimidazolyl, tetrazole, uridinyl and cytosinyl.
In another preferred embodiment, the heterocycle is a non-aromatic ring selected from the group consisting of pyrrolidine, imidazoline, 2-imidazolidone, 2-pyrrolidone, pyrrolin-2-one, tetrahydrofuran, 1,3-dioxolane, piperidine, tetrahydropyran, oxazoline, 1,3-dioxane, 1,4-piperazine, morpholine and thiomorpholine.
In another preferred embodiment in R2, substituents Rx and Ry are each hydrogen. Also preferred is R11, and R12 each being hydrogen. Still more preferred are compounds wherein n is 1 and nxe2x80x3 is 3-4.
In another preferred embodiment, n is 1-4.
In another preferred embodiment are compounds wherein:
R1 is vinyl, allyl, 3-methyl-2-butene or xe2x80x94(CH2)n-X, wherein n is 2-4, and X is a functionality selected from the group consisting of 
wherein R17 is H or C1-4alkyl;
(ii) xe2x80x94CH2xe2x80x94C6 H4-Z;
(iii) xe2x80x94(CH2)k-Zxe2x80x3, wherein k is 1-6; wherein Z and Zxe2x80x3 are each independently selected from the group consisting of: 
a and b are each independently 0-2; and
R15 and R16 are each independently H, C1-4alkyl, wherein said C1-4 alkyl is optionally substituted with 1-3 same or different halogens.
In another embodiment of the invention there is provided a method for treating mammals infected with RSV, and in need thereof, which comprises administering to said mammal a therapeutically effective amount of one or more of the aforementioned compounds of having Formula I, including pharmaceutically acceptable salts thereof.
Another embodiment includes a pharmaceutical composition which comprises a therapeutically effective amount of one or more of the aforementioned anti-RSV compounds of having Formula I, including pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
The term pharmaceutically acceptable salt includes solvates, hydrates, acid addition salts, base addition salts, and the salts of quaternary amines and pyridiniums. The acid addition salts are formed from a compound of Formula I and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, citric, malonic, fumaric, maleic, sulfamic, or tartaric acids. The counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate. The base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium and magnesium.
Halogen means bromine, chlorine, iodine and fluorine.